title: Predictors of asthma control and lung function responsiveness to step 3 therapy in children with uncontrolled asthma.
abstract: BACKGROUND
  Predictors of improvement in asthma control and lung function to step 3 therapy in children with persistent asthma have not been identified despite reported heterogeneity in responsiveness.
  
  
  OBJECTIVE
  We sought to evaluate potential predictors of asthma control and lung function responsiveness to step 3 therapy.
  
  
  METHODS
  A post hoc analysis from the Best Add-On Giving Effective Response (BADGER) study tested the association between baseline biological, asthma control, pulmonary function, and demographic markers and responsiveness to step-up to a higher dose of inhaled corticosteroid (ICS step-up therapy) or addition of leukotriene receptor antagonist (LTRA step-up therapy) or long-acting β₂-agonist (LABA step-up therapy).
  
  
  RESULTS
  In multivariate analyses higher impulse oscillometry reactance area was associated (P = .048) with a differential FEV₁ response favoring LABA over ICS step-up therapy, whereas higher urinary leukotriene E₄ levels were marginally (P = .053) related to a differential FEV₁ response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS with LTRA step-up therapy were not apparent, probably because of suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV₁ and asthma control day predictors, suggesting distinct mechanisms related to lung function and asthma control day responses.
  
  
  CONCLUSIONS
  Levels of impulse oscillometry reactance area indicating peripheral airway obstruction and urinary leukotriene E₄ levels indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up therapy. Further studies with physiologic, genetic, and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.
authors.affiliation: Department of Pediatrics, National Jewish Health and University of Colorado Denver School of Medicine, Denver, Colo. Electronic address: rabinovitchn@njhealth.org.
authors.forename: Nathan
authors.initials: N
authors.lastname: Rabinovitch
authors.affiliation: Department of Health Evaluation Sciences, Pennsylvania State University, Hershey, Pa.
authors.forename: David T
authors.initials: DT
authors.lastname: Mauger
authors.affiliation: Department of Pediatrics, National Jewish Health and University of Colorado Denver School of Medicine, Denver, Colo.
authors.forename: Nichole
authors.initials: N
authors.lastname: Reisdorph
authors.affiliation: Department of Pediatrics, National Jewish Health and University of Colorado Denver School of Medicine, Denver, Colo.
authors.forename: Ronina
authors.initials: R
authors.lastname: Covar
authors.affiliation: Department of Pediatrics, National Jewish Health and University of Colorado Denver School of Medicine, Denver, Colo.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Malka
authors.affiliation: University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lemanske
authors.affiliation: Arizona Respiratory Center, University of Arizona, Tucson, Ariz.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Morgan
authors.affiliation: University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: Theresa W
authors.initials: TW
authors.lastname: Guilbert
authors.affiliation: Department of Allergy, Kaiser Permanente, and the Department of Pediatrics, University of California-San Diego, San Diego, Calif.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Zeiger
authors.affiliation: Department of Pediatrics, Washington University, St Louis, Mo.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Bacharier
authors.affiliation: Department of Pediatrics, National Jewish Health and University of Colorado Denver School of Medicine, Denver, Colo.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Szefler
mesh_terms: D000085:Acetates / Q000008:administration & dosage; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives; D000730:Androstadienes / Q000008:administration & dosage; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000652:urine; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D002648:Child; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004804:Eosinophils / Q000166:cytology; D005260:Female; D000068298:Fluticasone; D005541:Forced Expiratory Volume; D006801:Humans; D007958:Leukocyte Count; D020024:Leukotriene Antagonists / Q000008:administration & dosage*; D017999:Leukotriene E4 / Q000652:urine; D008297:Male; D011804:Quinolines / Q000008:administration & dosage; D000068299:Salmeterol Xinafoate; D013440:Sulfides; D014797:Vital Capacity
chemical_list: D000085:Acetates; D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D013440:Sulfides; D000068299:Salmeterol Xinafoate; D017999:Leukotriene E4; D000068298:Fluticasone; C093875:montelukast; D000420:Albuterol
keywords: AACD; ACD; AX; Annualized asthma control day; Asthma; Asthma control day; BADGER; Best Add-On Giving Effective Response; FP; FVC; Feno; Fluticasone propionate; Forced vital capacity; Fraction of exhaled nitric oxide; ICS; IOS; Impulse oscillometry; Inhaled corticosteroids; Kilopascal per liter per second; LABA; LTRA; Leukotriene receptor antagonist; Long-acting β(2)-agonist; R5; Reactance area; Resistance at 5 Hz; Urinary leukotriene E(4); children; fraction of exhaled nitric oxide; impulse oscillometry; inhaled corticosteroids; kPa/L/s; leukotriene E(4); leukotriene receptor antagonist; long-acting β(2)-agonist; uLTE(4)